Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody-Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study

Abstract

Introduction: Patients with relapsed or refractory multiple myeloma (RRMM) represent an unmet clinical need. Belantamab mafodotin (belamaf; GSK2857916) is a first-in-class antibody-drug conjugate (ADC; or immunoconjugate) that delivers a cytotoxic payload, monomethyl auristatin F (MMAF), to myeloma cells. In the phase II DREAMM-2 study (NCT03525678), single-agent belamaf (2.5 mg/kg) demonstrated clinically meaningful anti-myeloma activity (overall response rate 32%) in patients with heavily pretreated disease. Microcyst-like epithelial changes (MECs) were common, consistent with reports from other MMAF-containing ADCs.

Methods: Corneal examination findings from patients in DREAMM-2 were reviewed, and the clinical descriptions and accompanying images (slit lamp microscopy and in vivo confocal microscopy [IVCM]) of representative events were selected. A literature review on corneal events reported with other ADCs was performed.

Results: In most patients receiving single-agent belamaf (72%; 68/95), MECs were observed by slit lamp microscopy early in treatment (69% had their first event by dose 4). However, IVCM revealed hyperreflective material. Blurred vision (25%) and dry eye (15%) were commonly reported symptoms. Management of MECs included dose delays (47%)/reductions (25%), with few patients discontinuing due to MECs (1%). The first event resolved in most patients (grade ≥2 MECs and visual acuity [each 77%], blurred vision [67%], and dry eye [86%]), with no reports of permanent vision loss to date. A literature review confirmed that similar MECs were reported with other ADCs; however, event management strategies varied. The pathophysiology of MECs is unclear, though the ADC cytotoxic payload may contribute to on- or off-target effects on corneal epithelial cells.

Conclusion: Single-agent belamaf represents a new treatment option for patients with RRMM. As with other ADCs, MECs were observed and additional research is warranted to determine their pathophysiology. A multidisciplinary approach, involving close collaboration between eye care professionals and hematologist/oncologists, is needed to determine appropriate diagnosis and management of these patients.

Trial registration: ClinicalTrials.gov Identifier, NCT03525678.

Keywords: Antibody–drug conjugate; Belantamab mafodotin; Cornea; In vivo confocal microscopy; Microcyst-like epithelial changes; Monomethyl auristatin F; Multiple myeloma; Oncology.

Fig. 1

Belamaf structure and mechanism of action. ADC antibody–drug conjugate, ADCC/ADCP antibody-directed cellular cytotoxicity/phagocytosis, BCMA B-cell maturation antigen, IgG1 immunoglobulin G1, mAb Monoclonal antibody, MM multiple myeloma, MMAF monomethyl auristatin F

Fig. 2

Time-to-recovery analysis for MECs in patients receiving belamaf (2.5 mg/kg) in DREAMM-2. EoT end of treatment, MEC microcyst-like epithelial changes. EoT defined as the last dose date (for patients with an unresolved event at treatment discontinuation) or the event onset date (for patients with an event that started post treatment discontinuation due to any reason). Analysis included patients who were not recovered at EoT exposure (defined as 20 days after the last infusion) and those who had events that started after treatment discontinuation (n = 39). Twenty-one percent (8/39) of patients died before recovery

Fig. 3

Representative slit lamp microscopic images of MECs. MECs microcyst-like epithelial changes. Slit lamp microscopic images (a–d) demonstrating MECs (see arrowheads). The lesions are small, located within the corneal epithelium, and are seen here in the corneal periphery and mid-periphery. Visualization requires high magnification and is aided by the use of retroillumination off the iris or indirect illumination

Fig. 4

Case report representative slit lamp and in vivo confocal microscopic images of MECs. MECs microcyst-like epithelial changes. Slit lamp microscopic images of the right (a) and left (b) eyes, demonstrating MECs (arrows). These lesions are best visualized at medium to high magnification. Retroillumination or indirect illumination can be helpful. In vivo confocal microscopic image from the same patient (c–f) demonstrating hyperreflective opacities within the corneal epithelium. These opacities were noted to be most prominent in the wing cells (d) and basal cells (e), as compared with the superficial cells (f). They were not visualized within the anterior stroma (f) or endothelium (not shown)

Fig. 5

Case report representative high-magnification fluorescein staining slit lamp microscopic images. Broad-beam slit lamp microscopic images with cobalt blue light demonstrating fluorescein staining of the right (a) and left (b) eyes. Whorl-like staining was noted in both corneas, most prominent in the inferonasal quadrant of the left eye (arrowhead)

Fig. 6

Change in BCVA over time with belamaf treatment in the DREAMM-2 case report. BCVA best-corrected visual acuity, KVA keratopathy and visual acuity, MECs microcyst-like epithelial changes. Corneal examination finding (MECs and changes in BCVA) were graded per KVA scale (Table 1), and represented (as grades 1–4) above each line for each examination

Fig. 7

Proposed mechanism of belamaf-associated MECs. Ep epithelium, BL Bowman’s layer, MECs microcyst-like epithelial changes, St stroma